Human APOBEC family members are important mediators of adaptive and innate immune responses. These proteins are defined by a highly conserved zinc-coordinating motif, HXE-X23-28-CX2-4C, in which the histidine and the two cysteines position zinc and the glutamate positions water to promote the nucleophilic deamination of cytosines within single-stranded, polynucleotide substrates (usually DNA). One family member, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G (A3G)), was identified as a cellular protein capable of blocking the replication of virion infectivity factor (Vif)-defective HIV-1. A3G inhibits the replication of HIV-1 and other retroviruses by deaminating viral cDNA cytosines to uracils during reverse transcription. Uracils template the incorporation of adenines during the synthesis of the complementary viral DNA strand, and subsequent replication (or DNA repair) ultimately produces strand-specific C/G to T/A transition mutations (hypermutations).